The field of the invention is nuclear magnetic resonance (NMR) spectroscopy, and particularly, methods and apparatus for producing two-dimensional and three-dimensional correlation spectra.
Atomic nuclei having net magnetic moments placed in static magnetic field B.sub.0, oscillate or precess about the axis of field B.sub.0 at an NMR (Larmor) frequency .omega. given by the equation EQU .omega.=.gamma.B.sub.0 ( 1)
in which .gamma. is the gyro-magnetic ratio (constant for each NMR isotope). The frequency at which the nuclei precess is thus proportional to the strength of the static magnetic field B.sub.0. Chemical shifts occur where the NMR frequency of resonant nuclei of the same type in a given molecule differ because of different magnetic environments produced by differences in their chemical environment. For example, electrons partially screen the nucleus from the magnetic field and thereby affect its resonant frequency. The degree of shielding caused by the electrons depends on the environment of the nucleus, and thus the chemical shift spectrum of a given molecule is unique and can be used for identification. Because the resonant frequency, hence the absolute chemical shift, is dependent on the strength of the applied field, the chemical shift spectrum is expressed as a fractional shift in parts-per-million (ppm) of the NMR frequency relative to an arbitrary reference compound. By way of illustration, the range of chemical shifts is about 10 ppm for protons (.sup.1 H). In order to discern such small chemical shifts, the homogeneity of field B.sub.0 must exceed the differences in chemical shifts of the peaks in the spectrum and typically is much better than 1 part in 10.sup.7 (0.1 ppm).
Another important characteristic of NMR spectra is scalar (or J) coupling. This through-bond interaction of nuclei gives rise to a fine structure which is observed as multiple splitting of resonances. These interactions give rise to multiple quantum energy states and can be exploited via 2 and 3 dimensional spectroscopy to correlate and identify resonances from nuclei which are connected through chemical bonds. These data are referred to as correlation maps.
To produce such correlation maps the NMR data is "frequency labelled" using a series of RF excitation pulses which maneuver the magnetization to take advantage of the couplings between adjacent hydrogen nuclei. One class of such measurements is known as "J-spectra" measurements and another class is known as "shift correlation" measurements. The present invention relates to this latter class of measurements.
One such well known 2D correlation NMR measurement, commonly called "COSY", is illustrated in FIG. 1. This sequence is characterized by a pair of 90.degree. RF excitation pulses which are separated by a time period t.sub.1 during which the transverse magnetization produced by the first RF pulse evolves. When the second RF pulse occurs, magnetization states are mixed and a coherence echo signal is observed at time 2t.sub.1 which is sampled over a time interval t.sub.2. In a 2D scan, a series of these measurements are conducted in which the evolution period t.sub.1 is incremented through a set of values ("dwell times") and a two-dimensional array of NMR data is acquired. A two-dimensional Fourier transform is then performed on this data producing a 2D spectrum which correlates chemical shifts. The signal on the diagonal of the 2D spectrum contains conventional, chemical shift information and off-diagonal signal ("cross-peaks") give the correlations.
While the COSY measurement is able to correlate coupled nuclei and produce a map which enables one to determine correlations, there are a number of constraints on this method which require that enormous amounts of data be acquired over prolonged periods of time. More specifically, each measurement must be made from 4 to 16 times for each value of t.sub.1 in a COSY sequence, and up to 128 times for more sophisticated sequences, such as double quantum filtered COSY ("DQ COSY"). For example, to eliminate axial peaks caused by residual longitudinal magnetization that is tipped into the transverse plane by the second RF pulse, a second measurement is made in which the phase of the second RF excitation pulse is reversed and the NMR data signals are added together. The desired signals add together and the signals produced by the residual longitudinal magnetization is cancelled. Also, to suppress quadrature images and other artifacts along the fl chemical shift axis, the phase of each RF pulse and the receiver are cycled in a procedure known as CYCLOPS and the four signals are combined. When CYCLOPS is combined with the axial peak suppression method, therefore, at least eight measurements at each t.sub.1 value must be made. If quadrature detection is desired, this number is increased to sixteen measurements and other procedures may require up to thirty-two measurements at each t.sub.1 value. As a result, the minimum number of measurements required for a typical 2D image may range from 8 to 32 and require from 30 to 120 minutes to perform.
In addition to the enormous amount of data that must be acquired and the lengthy time needed to acquire it, these "phase cycling" methods of selecting quantum coherence also presume that measurement conditions remain constant during the entire procedure. Such stability is required because phase cycling methods rely on subtractive techniques in which unwanted signals of equal magnitude are nulled, leaving the desired signal as the difference. In some cases stable measurement conditions cannot be maintained with sufficient accuracy to successfully use phase cycling sequences.
While the limitations in the prior art have been explained with respect to a particular single quantum coherence selection pulse sequence (COSY), it should be apparent to those skilled in the art that the problem exists in any pulse sequence in which quantum coherence is selected by the application of an RF excitation pulse to the spin system. Indeed, in higher order quantum coherence selection sequences it is not uncommon to require as many as 128 phase cycles to acquire accurate data for a single evolution period.